1. Field of the Invention
This invention is in the field of medical therapy. In particular, the invention relates to methods for treating, preventing, or reversing brain disease or damage produced by chronic alcohol intake or fetal exposure to alcohol by administering a peroxisome proliferator activated receptor (PPAR) agonist.
2. Related Art
Alcohol dependence and abuse are among the most costly healthcare problems in the world, and their impact continues to grow due to the rising incidence of heavy alcohol drinking among women and young people in general. Excessive drinking can cause cognitive dysfunction and permanent structural damage to the brain. Although Wernicke-Korsakoff syndrome is one of the most devastating and clinically significant forms of alcohol-associated neurodegeneration, its etiology is largely related to thiamine deficiency which is preventable. In contrast, the pathogenesis of more prevalent alcohol-associated brain lesions, including white matter attrition, ventriculomegaly, cerebellar degeneration, and neuronal loss within the superior frontal association cortex, anterior cingulate region, and hypothalamus, which result in cognitive and motor deficits, has not been determined.
In the central nervous system (CNS), neuronal survival, energy metabolism, and plasticity, which are critical for maintaining cognitive and motor functions, are regulated through the actions of insulin and insulin-like growth factors (IGF) types I and II. Insulin, IGF-I and IGF-II, and their corresponding receptors are abundantly expressed in various cell types throughout the brain, including neurons (Goodyer et al., Endocrinology 114:1187 (1984); Gammeltoft et al., Biochimie 67:1147 (1985); Hill et al., Neuroscience 17:1127 (1986)). In vitro and in vivo experiments demonstrated that insulin and IGF signaling pathways utilized by CNS neurons are virtually identical to those characterized in peripheral organs such as liver. The highest levels of insulin and IGF polypeptide and receptor gene expression in the brain are distributed in the hypothalamus, temporal lobe, and cerebellum, which notably represent major targets of ethanol neurotoxicity.
Studies involving the immature brain showed that ethanol inhibition of insulin and IGF signaling (Zhang et al., J. Neurochem. 71:196 (1998); de la Monte et al., Cell. Mol. Life Sci. 58:1950 (2001); de la Monte et al., Alcohol Clin. Exp. Res. 24:716 (2000); Hallak et al., Alcohol Clin. Exp. Res. 25:1058 (2001)) downstream through the PI3 kinase-Akt pathway (Zhang et al., J. Neurochem. 71:196 (1998); de la Monte et al., Cell. Mol. Life Sci. 58:1950 (2001); de la Monte et al., Cell. Mol. Life Sci. 59:882 (2002); Ramachandran et al., Alcohol Clin. Exp. Res. 25:862 (2001)) results in increased apoptosis (Ikonomidou et al. Science 287:1056 (2000); Zhang et al., J. Neurochem. 71:196 (1998); de la Monte et al., Cell. Mol. Life Sci. 58:1950 (2001)) and mitochondrial dysfunction (de la Monte et al., Cell. Mol. Life Sci. 58:1950 (2001); de la Monte et al., Cell. Mol. Life Sci. 59:882 (2002); Ramachandran et al., Alcohol Clin. Exp. Res. 25:862 (2001)). Ethanol inhibition of insulin signaling in the brain is mediated by insulin depletion and insulin/IGF resistance (Soscia et al., Cell. Mol. Life Sci., in press (2006)). Ethanol-induced insulin/IGF resistance is manifested by impaired ligand binding to the corresponding receptors, reduced activation of the receptor tyrosine kinases, and reduced signaling downstream through cell survival pathways. However, little is known about the effects of chronic ethanol abuse on insulin and IGF signaling mechanisms in the adult human brain.
Ethanol exposure during development is the leading preventable cause of mental retardation in Europe and North America. Heavy or chronic gestational exposure to ethanol causes fetal alcohol syndrome (FAS), which encompasses a broad array of neurological and systemic lesions including CNS malformations such as microencephaly, reduced cerebral white matter volume, ventriculomegaly, cerebellar hypoplasia, and disorders of neuronal migration (Clarren et al. J. Pediatr. 92:64 (1978); Mattson et al., Alcohol Res. Health 25:185 (2001)). However, much less is known about the full range of human CNS disease produced by lower levels of ethanol exposure due to the lack of accurate clinicopathological correlative data. Experimental models of FAS have provided insight about the range of ethanol-induced CNS abnormalities by demonstrating that gestational exposure to ethanol impairs neuronal survival, growth, migration, synaptogenesis, maturation, neurotransmitter function, and intracellular adhesion (Maier et al., Alcohol 23:49 (2001); Minana et al., J. Neurochem. 75:954 (2000); Olney et al., Apoptosis 5:515 (2000); Swanson et al., Alcohol Clin. Exp. Res. 19:1252 (1995); Yanni et al., Brain Res. Dev. Brain Res. 120:233 (2000); Liesi et al., J. Neurosci. Res. 48:439 (1997)). In addition, experimental models of FAS have provided evidence that ethanol can exert neurotoxic effects on the developing CNS, even after relatively short durations or low levels of exposure (Maier et al., Alcohol 23:49 (2001)). Therefore, with regard to human beings, there is concern that low or moderate levels of in utero ethanol exposure can have significant adverse effects on the developing brain, and may be responsible for the growing incidence of attention deficit/hyperactivity disorders (O'Malley et al., Can. J. Psychiatry 47:349 (2002); Burd et al., Neurotoxicol. Teratol. 25:697 (2003); Burd et al., Neurotoxicol. Teratol. 25:681 (2003)).
Neuronal genesis, differentiation, and migration are critical on-going processes likely to be perturbed by gestational exposure to ethanol. In the developing CNS, insulin, IGF-I, and IGF-II receptors are abundantly expressed (Goodyer et al., Endocrinology 114:1187 (1984); Gammeltoft et al., Biochimie 67:1147 (1985); Hill et al., Neuroscience 17:1127 (1986)), and their corresponding growth factors mediate neuronal growth, survival, energy metabolism, and synapse formation. In addition, there is growing evidence that insulin and IGF signaling mechanisms are key targets of ethanol-mediated neurotoxicity in the immature CNS (Zhang et al. J. Neurochem. 71:196 (1998); de la Monte et al. Cell. Mol. Life Sci. 58:1950 (2001); de la Monte et al., Alcohol Clin. Exp. Res. 24:716 (2000); Hallak et al., Alcohol Clin. Exp. Res. 25:1058 (2001)). Neuronal loss that is associated with ethanol-induced microencephaly is mediated by inhibition of insulin/IGF-I-stimulated survival signaling (Zhang et al., J. Neurochem. 0.71:196 (1998); de la Monte et al., Cell. Mol. Life Sci. 58:1950 (2001); de La Monte et al., Cell. Mol. Life Sci. 59:882 (2002); Ramachandran et al., Alcohol Clin. Exp. Res. 25:862 (2001)), and attendant increased apoptosis (Zhang et al., J. Neurochem. 71:196 (1998); de la Monte et al., Cell. Mol. Life Sci. 58:1950 (2001); Ikonomidou et al., Science 287:1056 (2000)) and mitochondrial dysfunction (de la Monte et al., Cell. Mol. Life Sci. 58:1950 (2001); de la Monte et al., Cell. Mol. Life Sci. 59:882 (2002); Ramachandran et al., Alcohol Clin. Exp. Res. 25:862 (2001); de la Monte et al. Alcohol Clin. Exp. Res. 25:898 (2001)).
Recent studies designed to divulge the mechanisms of ethanol-impaired insulin/IGF signaling in the developing brain demonstrated that chronic gestational exposure to relatively high levels of ethanol inhibit insulin gene expression, but produce only modest alterations in the expression of insulin and IGF-I receptors (de la Monte et al., Cell. Mol. Life Sci. 62:1131 (2005)). Although those results suggest that cell loss in ethanol-exposed developing brains may be mediated by a local deficiency of brain-derived insulin, the finding of reduced levels of insulin and IGF-I receptor tyrosine kinase activities following exogenous growth factor stimulation, suggests additional abnormalities contribute to the impairments in CNS development. Moreover, in vitro experiments demonstrated ethanol-inhibition of IGF-I and IGF-II, but not insulin receptor expression, yet insulin and IGF-I stimulated glucose uptake and ATP synthesis were similarly impaired (de la Monte et al., Cell. Mol. Life Sci. 62:1131 (2005)). Therefore, the mechanisms by which ethanol adversely affects insulin and IGF-I responsiveness in neurons require further investigation.